This is an updated clinical practice guideline for the empirical management of fever and neutropenia (FN) in children with cancer and hematopoietic stem-cell transplantation recipients.

Description

The International Pediatric Fever and Neutropenia Guideline Panel has put together this guideline (FN CPG). For questions of risk stratification and evaluation, systematic reviews of observational studies were updated. They conducted a systematic review of randomized trials of any intervention applied for the empirical management of pediatric FN. Recommendations and quality of evidence is listed throughout the manuscript.

Results Summary

Recommendations related to initial presentation, ongoing management, and empirical antifungal therapy of pediatric FN were reviewed; the most substantial changes were related to empirical antifungal therapy from the 2012 guideline. Summary of the major changes from the previous 2012 guideline:
1) Peripheral blood cultures concurrently with central venous catheter cultures: quality of evidence increased to moderate from low.
2) Use of monotherapy with beta-lactam, a fourth generation cephalosporin or a carbapenem as empirical therapy in pediatric high risk FN: fourth generation cephalosporin added
3) Patients at high risk of invasive fungal disease (IFD) are those with AML, HR-ALL, or relapsing acute leukemia and children undergoing HSCT. Also those with prolonged neutropenia and high-dose corticosteroids are at high risk of IFD. All other should be categorized as IFD low-risk: risk factors refined. Quality of evidence decreased to low from moderate.
4) Consider not using serum Galactomannan (GM) : now weak recommendation against GM
5) Do not use fungal PCR testing in blood: new recommendation, poor PPV and NPV not significantly high enough to be clinically useful. PCR testing not yet standardized
6) Perform CT of the lungs for IFD work-up: quality of evidence decreased to low from moderate. Lungs are consistently the most commonly affected site. Optimal timing of initial and repeated imaging not known.
7) Consider imaging of abdomen in patients without localizing signs or symptoms of IFD: New recommendation, ideal imaging modality not known.
8) Consider not routinely performing CT of sinuses if no localizing signs or symptoms of IFD: Now weak recommendation against CT sinuses
9) In IFD low-risk patients with prolonged (greater than or equal to 96 hours) FN, consider withholding empirical antifungal therapy: now weak recommendation against empirical therapy for IFD low-risk patients.

Limitations

The main research gaps are listed in Table 2 of the article and fall into 3 major categories:
1) Initial presentation
Optimal temperature threshold to define fever
New serum biomarkers as diagnostic and monitoring aids
2) Ongoing management
Timing and necessity of repeated blood cultures for persistent fever
Duration of empirical antibiotics for low and high risk FN
Role of providing targeted antibiotics only vs. continuing broad-spectrum coverage in patients with positive cultures who remain neutropenic
Determining whether the diagnostic and therapeutic approach should differ between patients with prolonged continuous fever vs. recurrent fever during FN
3) Empirical antifungal management
Role of combination biomarkers for IFD evaluation and ongoing management
Identifying novel biomarkers for IFD detection
Role and timing of standard imaging on patient outcomes
Efficacy and safety of pre-emptive antifungal therapy
Appropriate duration of empirical antifungal therapy
Determining appropriate pediatric dosing for currently available antifungal agents, and identifying novel antifungal agents for empirical therapy

Overall, Cost effectiveness of different approaches to manage pediatric FN.

Bottom Line

Key differences as summarized above from 2012 FC CPG tot he 2017 FC CPG. Implementation will be the next step. Further decision making may be further guided by cost-effectiveness studies. Individual clinician's experience will be a key influencing factors to implementation and adoption of the new FN guidelines.